Abstract
Abstract Background: O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) encodes the DNA-repair protein O6-alkylguanine (O6-AG) DNA alkyltransferase (AGT) that repair DNA adducts caused by alkylating agents. MGMT has important implications in cancer treatment since its expression induces resistance to methylating and chloroethylating anticancer drugs which are effective treatment options in tumours lacking MGMT expression. The demand to find agents that induce MGMT deficiency and increase the susceptibility to alkylating chemotherapeutic agents is therefore highly warranted. Methods: The correlation between Wnt activity and MGMT expression was investigated in primary medulloblastomas, gliomas and colon cancer using gene expression cohorts. Cell lines from medulloblastomas, gliomas, colon cancer and neuroblastomas were examined for Wnt/β-catenin activity and MGMT expression using immunoblotting and Real-Time quantitative PCR (Q-PCR). Small interfering RNA (siRNA) against β-catenin, forced overexpression of β-catenin, and MGMT promotor reporter plasmids were used to study β-catenin mediated regulation on MGMT. Cell cytotoxicity and clonogenicity of chemotherapeutic drugs in combination with celecoxib were examined in cell lines using fluorometric microculture cytotoxicity assay and clonogenic assay, respectively. In vivo, nude NMRI mice carrying D283 MED xenografts were treated with celecoxib in combination with temozolomide. Results: Wnt signaling activity was shown to be correlated to increased MGMT expression levels both in primary tumors and cell lines of different origins. Transfection experiments revealed that β-catenin regulates MGMT expression. Proinflammatory prostaglandin E2 activates the Wnt/β-catenin cascade and increase MGMT expression. The clinically available COX-2 inhibitor celecoxib augmented the cytotoxic effect of the DNA alkylating drug, temozolomide in cells with elevated MGMT expression both in vitro and in established medulloblastoma xenografts in nude mice through inhibition of Wnt/β-catenin activity and subsequent reduction in MGMT expression. Conclusions: This study demonstrates that celecoxib reduces the transcription of the MGMT gene through a prostaglandin E2-Wnt/β-catenin route and thus increases the susceptibility to temozolomide. These finding are the first reported that Wnt/β-catenin pathway regulates the expression of MGMT and thus provides a rational approach for improved efficacy of chemotherapeutic drugs inducing DNA alkylation in cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-209. doi:10.1158/1538-7445.AM2011-LB-209
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